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Figure 1

Figure 1. From: Transcription-induced DNA double strand breaks: both oncogenic force and potential therapeutic target?.

An emerging model suggests that efficient induction of transcriptional programs can involve the generation of DNA double strand breaks and perhaps other DNA damage, repair of these breaks via recruitment of DNA repair proteins, and large scale movement of genes and regulatory elements to transcriptional hubs, in which transcription (co)factors are present at high local concentration. These events are illustrated for induction of transcriptional programs by AR. Upon transcriptional activation, AR associates with TOP2B and binds to AR target sites. DNA repair proteins including Ku70, Ku80, PARP1, ATM and DNA-PK and possibly other DNA repair enzymes also get recruited to these sites. TOP2B can mediate DSB in associated DNA. Reactive oxygen, perhaps generated during AR signaling, dietary carcinogens, and collision with the replication or transcription forks can transform these transient breaks into frank double strand breaks. Persistence of these breaks can result in induction of cellular senescence and apoptosis. Illegitimate repair of these breaks can lead to the formation of structural rearrangements. Such pathways are likely at work for other induced transcriptional programs, including those mediated by ER, RAR, and AP1.

Michael C. Haffner, et al. Clin Cancer Res. ;17(12):3858-3864.

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